Novel compounds for treating proliferative diseases

Abstract

The invention provides novel compounds that are inhibitors of PDK1. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or compositions.

1 . A compound of Formula (Ia): 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt thereof, wherein: 
       R 1a  is selected from H and halogen; 
       R 3a  is selected from C 2-6  heterocycloalkyloxy and C 1-6  heteroaryl-C 1-4 -alkoxy; wherein said C 2-6  heterocycloalkyloxy and C 1-6  heteroaryl-C 1-4 -alkoxy are each optionally substituted by a R w  group; 
       R 4a  is selected from H, a thiazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, a pyridine ring, C 3-6  cycloalkyl, cyano, halogen, C 2-6  alkynyl, C 1-6  heteroaryl-C 1-4 -alkyl, C 1-6  heteroaryl-C 1-4 -alkynyl, —C(═O)R a , and —C(═O)NR b R c ; wherein said thiazole ring, pyrazole ring, triazole ring, tetrazole ring, pyridine ring, C 1-6  heteroaryl-C 1-4 -alkyl and C 1-6  heteroaryl-C 1-4 -alkynyl are each optionally substituted by 1 or 2 independently selected R x″  groups; 
       Ar 1a  is selected from phenyl optionally substituted at the meta position by one R y′  or, alternatively, at the para position by one R y″  group; 
       each R w  is independently selected from halogen, C 1-6  alkyl, amino, C 1-6  alkylamino, di-C 1-4 -alkylamino, C 1-6  alkoxycarbonyl, and C 1-6  alkylcarbamyl; wherein said C 1-6  alkyl and C 1-6  alkylamino are each optionally substituted by a group selected from hydroxyl, C 1-6  alkoxy, amino, C 1-6  alkylamino, and di-C 1-4 -alkylamino; 
       each R x″  is independently selected from halogen, hydroxyl, C 1-6  alkyl, C 1-6  alkoxycarbonyl, and carbamyl; wherein said C 1-6  alkyl and C 1-6  alkoxycarbonyl are each optionally substituted by a group selected from hydroxyl, amino, C 1-4  alkylamino, and aminosulfonyl; 
       R y′  is selected from halogen, C 1-6  alkoxy, C 1-6  alkyl, carbamyl, aminosulfonyl, and C 1-6  alkylsulfonylamino; wherein said C 1-6  alkyl and C 1-6  alkoxy are each substituted by 1 or 2 groups independently selected from hydroxyl, amino, C 1-4  alkylamino, and aminosulfonyl; 
       R y″  is selected from C 1-6  haloalkyl; 
       R a  is selected from H, C 1-6  alkoxy and C 2-6  heterocycloalkyl; 
       R b  is selected from H and C 1-6  alkyl; and 
       R c  is selected from C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  heteroaryl, C 2-6  heterocycloalkyl, C 2-6  heterocycloalkyl-C 1-4 -alkyl, and C 1-6  heteroaryl-C 1-4 -alkyl; wherein said C 1-6  alkyl is optionally substituted by a group selected from hydroxyl and C 1-4  alkoxy; 
       provided that:
 (a) when R 3a  is piperidin-4-yloxy or N-methylpiperidin-4-yloxy, then R 4  is not selected from thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 5-methylthiazol-2-yl, 5-(hydroxymethyl)thiazol-2-yl, 5-(hydroxymethyl)thiazol-4-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, 4-methylpyridin-3-yl, 5-chloropyridin-4-yl, 3-methylpyridin-2-yl, and 1-methylpyrazol-5-yl; 
 (b) when R 4a  is ethynyl and Ar 1a  is 3-fluorophenyl, then R 3  is not selected from pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, pyridin-2-ylmethoxy, pyridin-4-ylmethoxy, 1-(pyridin-4-yl)ethoxy, 6-methoxypyridin-2-ylmethoxy, thiazol-5-ylmethoxy, pyrazin-2-ylmethoxy, 5-methylisooxazol-3-yl, azetidin-3-yloxy, N-methylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methyl, and pyrrolidin-3-yloxy; 
 (c) when R 4a  is ethynyl, then Ar 1a  is not selected from 3-(2-hydroxypropan-2-yl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-amino sulfonylphenyl, phenyl, 3-(methylsulfonylamino)phenyl, 3-(N,N-dimethylaminomethyl)phenyl, 3-aminosulfonylphenyl, and 3-carbamylphenyl; 
 (d) when R 4a  is thiazol-2-yl, then Ar 1a  is not selected from 3-(methylaminosulfonyl)phenyl, 3-chlorophenyl, 3-carbamylphenyl, 3-fluorophenyl, 2-(hydroxypropan-2-yl)phenyl, 1-hydroxyethyl, 3-aminosulfonylphenyl, and phenyl; 
 (e) when R 4a  is thiazol-2-yl and Ar 1a  is 3-fluorophenyl, then R 3  is not selected from pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, 2-chloropyridin-4-ylmethoxy, 5-methylisooxazol-3-yl, azetidin-3-yloxy, N-methylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, and N-methylpiperidin-4-yloxy; 
 (f) when R 4a  is bromo, then Ar 1a  is not selected from phenyl, 3-fluorophenyl, 2-(hydroxypropan-2-yl)phenyl, 1-hydroxyethyl, and 3-amino sulfonylphenyl ; 
 (g) when R 4a  is cyano, then R 3a  is not selected from pyridin-4-ylmethoxy, pyridin-2-ylmethoxy, and 6-methoxypyridin-2-ylmethoxy; 
 (h) when R 4a  is cyclopropyl, then R 3a  is not selected from azetidin-3-yloxy; and 
 (i) when R 4a  is hydrogen, then Ar 1a  is 3-(aminosulfonyl)phenyl. 
 
     
   
   
       2 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein Ar 1a  is selected from 3-fluorophenyl, 3-methylaminosulfonyl, 3-carbamylphenyl, 3-chlorophenyl, 4-difluoromethylphenyl, -(2-amino-n-propyl)methylphenyl, 3-(1-amino-3-hydroxy-n-propyl)phenyl, 3-(2-aminoethyl)phenyl, 3-(aminomethyl)phenyl, 3-(3-amino-1-hydroxy)phenyl, 3-(2-hydroxyethyl)phenyl, 3-(hydroxymethyl)phenyl, 3-methylaminosulfonyl, 3-(aminosulfonylmethyl)phenyl, 3-carbamylphenyl and 3-chlorophenyl. 
   
   
       3 . The compound according to any one of  claims 1  and  2 , or pharmaceutically acceptable salt thereof, wherein R 3a  is selected from piperidin-4-yloxy, N-methylpiperidin-4-yloxy, N-(tert-butoxycarbonyl)piperidin-4-yloxy, 3-fluoropiperidin-4-yloxy, 2-(hydroxymethyl)piperidin-4-yloxy, N-(tert-butoxycarbonyl)piperidin-4-yl, 2-(N-methylcarbamyl)piperidin-4-yloxy, 6-methoxypyridin-3-ylmethoxy, 6-(N-methylamino)pyridin-3-ylmethoxy, 6-(N,N-dimethylamino)pyridin-3-ylmethoxy, 6-(N-(2-hydroxyethyl)amino)pyridin-3-ylmethoxy, 6-(N-(2-methoxyethyl)amino)pyridin-3-ylmethoxy, 6-(N-(2-aminoethyl)amino)pyridin-3-ylmethoxy, and pyridin-3-ylmethoxy; and
 R 4a  is selected from ethynyl, bromo, cyano, cyclopropyl, thiazol-2-yl, pyridin-3-yl, 4-(hydroxymethyl)thiazol-2-yl, 1,2,3-triazol-5-yl, tetrazol-5-yl, pyrazol-2-yl, 5-methylpyrazol-2-yl, 2-(pyridin-2-yl)ethynyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethynyl, 2-(pyridin-3-yl)ethyl, 4-(methoxycarbonyl)thiazol-2-yl, 4-carbamylthiazol-2-yl, —C(═O)R a , and —C(═O)NR b R c .   
   
   
       4 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is 3-fluorophenyl;   R 3a  is selected from 3-fluoropiperidin-4-yloxy, 2-(hydroxymethyl)piperidin-4-yloxy, N-(tert-butoxycarbonyl)piperidin-4-yl, and 2-(N-methylcarbamyl)piperidin-4-yloxy; and   R 4a  is selected from thiazol-2-yl and pyridin-3-yl.   
   
   
       5 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is 3-fluorophenyl;   R 3a  is selected from 6-methoxypyridin-3-ylmethoxy, 6-(N-methylamino)pyridin-3-ylmethoxy, 6-(N,N-dimethylamino)pyridin-3-ylmethoxy, 6-(N-(2-hydroxyethyl)amino)pyridin-3-ylmethoxy, 6-(N-(2-methoxyethyl)amino)pyridin-3-ylmethoxy, and 6-(N-(2-aminoethyl)amino)pyridin-3-ylmethoxy; and   R 4a  is ethynyl.   
   
   
       6 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is selected from 3-(2-amino-n-propyl)methylphenyl, 3-(1-amino-3-hydroxy-n-propyl)phenyl, 3-(2-aminoethyl)phenyl, 3-(aminomethyl)phenyl, 3-(3-amino-1-hydroxy)phenyl, 3-(2-hydroxyethyl)phenyl, and 3-(hydroxymethyl)phenyl;   R 3a  is selected from pyridin-3-ylmethoxy; and   R 4a  is selected from ethynyl and bromo.   
   
   
       7 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is selected from 3-methylaminosulfonyl, 3-(aminosulfonylmethyl)phenyl, and phenyl;   R 3a  is selected from piperidin-4-yloxy; and   R 4a  is thiazol-2-yl and 4-(hydroxymethyl)thiazol-2-yl.   
   
   
       8 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is 3-fluorophenyl   R 3a  is selected from piperidin-4-yloxy and N-(tert-butoxycarbonyl)piperidin-4-yloxy;   R 4a  is selected from —C(═O)R a , and —C(═O)NR b R c ;   R a  is selected from H, methoxy and morpholin-4-yl;   R b  is selected from H and methyl; and   R c  is selected from methyl, 2-hydroxyethyl, 2-methoxyethyl, tetrahydro-2H-pyran, tetrahydropyran-2H-methyl, 2-oxopyrrolidinylethyl, and pyridin-3-ylmethyl;   
   
   
       9 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 R 1a  is selected from H;   Ar 1a  is 3-carbamylphenyl and 3-chlorophenyl;   R 3a  is selected from pyridin-4-ylmethoxy; and   R 4a  is selected from ethynyl and bromo.   
   
   
       10 . A compound of Formula (IIa): 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from H and halogen 
 R 2  is selected from H, halogen, and C 1-6  alkoxy; 
 R 3  is selected from H, —OCH 2 -phenyl, —O—CH 2 -Het, —OCH 2 —CH 2 -Het, and —O—Hy; wherein Het is 6-membered heteroaryl which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-C 1-4  alkylamino, and C 1-6  alkylcarbamyl; Hy is 6-membered heterocycloalkyl, which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-C 1-4  alkylamino, and C 1-6  alkylcarbamyl; and phenyl is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-C 1-4  alkylamino, and C 1-6  alkylcarbamyl; 
 R 4  is selected from cyano, halogen, C 1-6  alkyl, C 2-6  alkynyl, C 3-6  cycloalkyl, a thiazole ring, a pyrazole ring, and a pyridine ring; each of which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, and di-C 1-4  alkylamino; wherein said C 1-6  alkyl is further optionally substituted by 1 or 2 hydroxyl groups; 
 Ar 1  is a moiety of Group (A), (B), or (C): 
 
     
     
       
         
         
             
             
         
       
       
         A is a pyrazole ring; which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, and di-C 1-4  alkylamino; 
         A′ is selected from -L 2 -Ar 2  and -L 1 -Cy 1 ; 
         A″ is selected from L 2a -Ar 2a  and Cy 1a ; 
         L 1  is selected from a bond, —O—, —C(═O)—, —CH 2 C(═O)—, and —CH 2 —; wherein the left end of the linker is attached to the phenyl ring and the right end of the linker is attached to Cy 1 ; 
         Cy 1  is selected from a morpholine ring, a tetrahydro-2H-pyran ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, and a piperidine ring, each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-C 1-4  alkylamino, C 1-6  alkylcarbonyl, and C 1-6  alkoxycarbonyl; 
         Cy 1a  is selected from a morpholine ring, a 2-oxopyrrolidine ring and a piperidine ring; each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-C 1-4  alkylamino, C 1-6  alkylcarbonyl, and C 1-6  alkoxycarbonyl; 
         L 2  and L 2a  are each independently selected from a bond, —O—, and —CH 2 —; and 
         Ar 2  is selected from a pyrazole ring, an oxazole ring, an imidazole ring, a triazole ring, a thiadiazole ring, a pyridine ring, and a pyrimidine ring; each of which is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, and di-C 1-4  alkylamino; 
         Ar 2a  is selected from a pyrazole ring, a triazole ring, a pyridine ring, and a pyrimidine ring; each of which is optionally substituted with 1 or 2 groups independently selected from hydroxyl, C 1-6  alkyl, C 1-4  alkoxy, amino, C 1-4  alkylamino, and di-C 1-4  alkylamino; 
       
       provided that: 
       (i) when R 1  and R 2  are each H, R 4  is thiazol-2-yl, R 3  is optionally substituted piperidin-4-yloxy, and Ar 1  is a moiety of Group (A), then A′ is not selected from 1,2,4-triazol-1-ylmethyl, 1-methylpyrazol-3-yl, 2-oxopyrrolidinyl, oxazol-5-yl, pyrazol-1-yl, 1-methyl-1,2,4-triazol-2-yl, morpholin-4-ylcarbonylmethyl, imidazol-2-yl, 2-methylthiazol-4-yl, 1,3,5-trimethylpyrazol-4-yl, pyrimidin-5-yl, 1,2,4-triazol-1-yl, 4,5-dimethyloxazol-2-yl, pyrimidin-5-yl, 2-methoxypyrimidin-5-yl, 6-methoxypyridin-3-yl, and pyridin-3-yl; 
       (ii) when R 1  and R 2  are each H, Ar 1  is a moiety of Group (A), A′ is selected from 1-methylpyrazol-3-yl, and R 3  is selected from pyridin-3-ylmethoxy and pyrazin-2-ylmethoxy, then R 4  is not thiazol-2-yl; 
       (iii) when R 1  and R 2  are each H, R 4  is thiazol-2-yl, R 3  is optionally substituted piperidin-4-yloxy, and Ar 1  is a moiety of Group (B), then A″ is not selected from morpholin-4-yl, morpholin-4-ylcarbonylmethyl, pyrimidin-5-yl, and pyrazol-1-ylmethyl; 
       (iv) when R 1  and R 2  are each H, R 4  is bromo, R 3  is pyridin-3-ylmethyl, and Ar 1  is a moiety of Group (A), then A′ is not piperidin-4-yl; 
       (v) when R 1  and R 3  are each H, R 4  is bromo or ethynyl, R 2  is isopropoxy, and Ar 1  is a moiety of Group (A), then A′ is not selected from 1-methyl-1,2,4-triazol-2-ylmethyl and morpholin-4-ylcarbonylmethyl; 
       (vi) when R 1  and R 2  are each H, R 4  is cyclopropyl, bromo or ethynyl, R 3  is chloro, and Ar 1  is a moiety of Group (A), then A′ is not 1,2,4-triazol-1-ylmethyl; 
       (vii) when R 1  and R 2  are each H, R 4  is ethynyl, R 3  is chloro, and Ar 1  is a moiety of Group (A), then A′ is not imidazol-2-yl, pyrazol-1-yl, and morpholin-4-ylmethyl; 
       (viii) when R 1  and R 3  are each H, R 4  is ethynyl, R 1  is chloro, and Ar 1  is a moiety of Group (A), then A′ is not selected from pyrazol-1-yl, oxazol-5-yl, imidazol-2-yl, morpholin-4-ylcarbonylmethyl, and 2-oxopyrrolidinyl; 
       (ix) when R 1  and R 2  are each H, R 4  is ethynyl, R 3  is H, and Ar 1  is a moiety of Group (A), then A′ is not selected from 1,2,4-triazol-1-ylmethyl, pyrazol-1-yl, oxazol-5-yl, imidazol-2-yl, 5-trifluoromethylimidazol-2-yl, imidazol-1-ylmethyl, 1,2,4-triazol-1yl-methyl, N-(ethoxycarbonyl)piperidin-4-yl, N-(methoxycarbonyl)piperidin-4-yl, N-(acetyl)piperidin-4-yl, N-methylpiperidin-4-yl, piperidin-4-yl, and 2-oxopyrrolidinyl; 
       (x) when R 1  and R 2  are each H, R 4  is ethynyl, Ar 1  is a moiety of Group (A), and A′ is 1-methylpyrazol-3-yl, then R 3  is not selected from pyridin-3-ylmethoxy, 2-pyridin-3-ylethoxy, thiazol-5-ylmethoxy, and pyrazin-2-ylmethoxy; 
       (xi) when R 1  and R 2  are each H, R 4  is ethynyl, Ar 1  is a moiety of Group (A), and A′ is morpholin-4-ylmethyl, then R 3  is not selected from pyridin-3-ylmethoxy and pyrazin-2-ylmethoxy; 
       (xii) when R 1  and R 2  are each H, R 4  is ethynyl, Ar 1  is a moiety of Group (A), and A′ is oxazol-5-yl, then R 3  is not selected from pyridin-3-ylmethoxy and pyrazin-2-ylmethoxy; 
       (xiii) when R 1  and R 2  are each H, R 4  is ethynyl, R 3  is H, and Ar 1  is a moiety of Group (B), then A″ is not selected from morpholin-4-ylmethyl and 2-oxopyrrolidinyl; 
       (xiv) when R 1  and R 2  are each H, R 4  is ethynyl, R 3  is chloro, and Ar 1  is a moiety of Group (B), then A″ is not selected from 2-oxopyrrolidinyl and morpholin-4-ylmethyl; 
       (xv) when R 1  and R 2  are each H, R 3  is pyrazin-2-ylmethoxy, R 4  is pyrazol-4-yl, and Ar 1  is a moiety of Group (A), then A′ is not 1-methylpyrazol-3-yl; 
       (xvi) when R 1  and R 2  are each H, R 3  is piperidin-4-yloxy or N-methylpiperidin-4-yloxy, R 4  is pyrazol-4-yl, and Ar 1  is a moiety of Group (B), then A″ is not morpholin-4-yl; 
       (xvii) when Ar 1  is 3-morpholin-4-ylphenyl, then R 3  is not H; 
       (xviii) when Ar 1  is 4-morpholin-4-ylphenyl, then R 4  is not selected from bromo, cyano, ethynyl, thiazol-2-yl, and 1H-pyrazol-4-yl; 
       (xix) when R 1′  is H, R 2′  is H, R 3′  is piperidin-4-yloxy, and R 4′  is 6-methoxypyridin-3-yl, and Ar 1  is a moiety of Group (A), then A′ is not 6-methoxypyridin-3-yl; and 
       (xx) when R 1′  is H, R 2′  is H, R 3′  is piperidin-4-yloxy, and R 4′  is 5-methoxypyridin-3-yl, and Ar 1  is a moiety of Group (B), then A″ is not 5-methoxypyridin-3-yl. 
     
   
   
       11 . The compound according to  claim 14 , or pharmaceutically acceptable salt thereof, wherein Ar 1  is a moiety of Group (A). 
   
   
       12 . The compound according to  claim 11 , or pharmaceutically acceptable salt thereof, wherein A′ is -L 2 -Ar 2 . 
   
   
       13 . The compound according to  claim 11 , or pharmaceutically acceptable salt thereof, wherein A′ is -L 1 -Cy 1 . 
   
   
       14 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 2 -Ar 2 ;   L 2  is a bond;   Ar 2  is selected from a pyridine ring, a pyrimidine ring, 1H-pyrazole ring, an oxazole ring, a 1,2,4-triazole ring, and a thiadiazole ring; each of which is optionally substituted by 1 or 2 groups independently selected from C 1-6  alkyl and C 1-6  alkoxy;   R 1  is H;   R 2  is H;   R 3  is selected from —O-phenyl, —O—CH 2 -Het, —OCH 2 —CH 2 -Het, and —O—Hy; wherein Het is a pyrazine ring, a pyridine ring, a pyrimidine ring, or a pyridazine ring; which is optionally substituted by a C 1-6  alkyl group; Hy is piperidine ring, which is optionally substituted by a C 1-6  alkyl group; and phenyl is optionally substituted by a C 1-6  alkylcarbamyl group; and   R 4  is selected from C 2-6  alkynyl, thiazol-2-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-3-yl.   
   
   
       16 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 2 -Ar 2 ;   L 2  is a bond;   Ar 2  is selected from 5-methoxypyridin-3-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, oxazol-5-yl, 1,2,4-triazol-5-yl, thiadiazol-4-yl, and 1-methyl-1H-pyrazol-3-yl;   R 1  is H;   R 2  is H;   R 3  is selected from piperidin-4-yloxy, N-methylpiperidin-4-yloxy, 3-(N-methylcarbamyl)benzyloxy, pyrazin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridimidin-5-ylmethoxy, pyridazin-3-ylmethoxy, and pyrazin-2-ylethoxy; and   R 4  is selected from ethynyl, thiazol-2-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-3-yl.   
   
   
       17 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 2 -Ar 2 ;   L 2  is —CH 2 —;   Ar 2  is selected from 1,2,4-triazol-1-yl, 1H-pyrazol-1-yl, and 1H-imidazol-1-yl ; each of which is optionally substituted by 1 or 2 independently selected C 1-6  alkyl groups;   R 1  is H;   R 2  is H;   R 3  is selected from pyrazin-2-ylmethoxy, pyridin-3-ylmethoxy, pyrazin-2-ylethoxy, and pyrimidin-5-ylmethoxy; and   R 3  is selected from —O—CH 2 -Het and —OCH 2 —CH 2 -Het; wherein Het is a pyrazine ring, a pyridine ring, or a pyrimidine ring; which is optionally substituted by a C 1-6  alkyl group; and   R 4  is selected from C 2-6  alkynyl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, and 1-methyl-1H-pyrazol-5-yl.   
   
   
       18 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 1 -Cy 1 ;   L 1  is selected from —CH 2 — and —CH 2 C(═O)—;   Cy 1  is selected from morpholin-4-yl; which is optionally substituted by 1 or 2 independently selected C 1-6  alkyl groups;   R 1  is H;   R 2  is H;   R 3  is selected from —O—CH 2 -Het and —OCH 2 —CH 2 -Het; wherein Het is a pyrazine ring, a pyridine ring, or a pyrimidine ring; which is optionally substituted by a C 1-6  alkyl group; and   R 4  is selected from C 2-6  alkynyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-3-yl.   
   
   
       19 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 1 -Cy 1 ;   L 1  is selected from —CH 2 — and —CH 2 C(═O)—;   Cy 1  is morpholin-4-yl;   R 1  is H;   R 2  is H;   R 3  is selected from pyrazin-2-ylmethoxy, pyridin-3-ylmethoxy, pyrimidin-5-ylmethoxy, and pyrazin-2-ylethoxy; and   R 4  is selected from ethynyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-3-yl.   
   
   
       20 . The compound according to  claim 13 , or pharmaceutically acceptable salt thereof, wherein:
 A′ is -L 1 -Cy 1 ;   L 1  is —C(═O)—;   Cy 1  is selected from a morpholine ring; which is optionally substituted by 1 or 2 independently selected C 1-6  alkyl groups;   R 1  is H;   R 2  is H;   R 3  is selected from —O—CH 2 -Het and —OCH 2 —CH 2 -Het; wherein Het is a pyrazine ring; which is optionally substituted by a C 1-6  alkyl group; and   R 4  is selected from cyano, methyl, C 2-6  alkynyl, C 3-6  cyclopropyl, 1-methyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-3-yl.   
   
   
       21 . Use of a compound according to any one of  claims 1  to  20 , for the preparation of medicament for use in a method of treating a cancer selected from lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer; uterine corpus cancer; uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma. 
   
   
       22 . Use of a compound according to any one of  claims 1  to  20 , for the preparation of medicament for use in a method of inhibiting PDK1 or a PDK1 variant in an individual. 
   
   
       23 . A compound according to any one of  claims 1  to  20 , for use in a method Of treating a cancer selected from lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer; uterine corpus cancer; uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma. 
   
   
       24 . A compound according to any one of  claims 1  to  20 , for use in a method of a treating a disease selected from neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis and endotoxic shock. 
   
   
       25 . A compound according to any one of  claims 1  to  20 , for use in a method of inhibiting the tumor growth in an individual. 
   
   
       26 . A compound according to any one of  claims 1  to  20 , for use in a method of inhibiting PDK1 or a PDK1 variant in an individual.